PROJECT SUMMARY ? DISCOVERY AND ANALYSIS PROGRAM ABSTRACT Here we describe the Discovery and Analysis Program for the National Center for the Identification and Study of Individuals with Atypical Diabetes Mellitus. The purpose of the project is to bring together internationally recognized diabetes investigators with expertise in the pathophysiology and genetics of diabetes to: A) Foster the study of individuals with rare/atypical forms of diabetes mellitus and B) Identify and analyze rare phenotypes and genotypic variants of diabetes that may ultimately provide insights into more prevalent, heterogeneous forms of type 2 diabetes mellitus (T2DM) in the general population. The central hypothesis of the entire center is that the identification and study of new cases of rare/atypical forms of diabetes will yield greater insights into the etiology and genetic heterogeneity of T2DM. To reach the goals of this project, building on the track records of the participating groups over the last three decades, we will seek to accomplish the following Specific Aims: (1) Identify and enroll individuals/families (children and adults) with rare/atypical forms of diabetes utilizing a unified ascertainment protocol supported by the resources and expertise from participating diabetes centers; (2) Characterize novel diabetes genes/variants in the cohort associated with new rare/atypical forms of diabetes and identify pre-symptomatic at-risk members of the family; and (3) Characterize the cardinal features and phenotypic spectrum associated with the identified novel genes/variants and evaluate age-related disease penetrance. The general approach is to promulgate a strategy for identification of rare/atypical forms, filter out primary autoimmune and known monogenic forms, and further characterize the remainder. Deeper phenotyping and genomic characterization of these individuals and their families in subsequent studies should help to characterize milder or otherwise atypical subtypes present in the spectrum of T2DM in the general population and reveal novel mechanistic pathways involved in the pathogenesis of diabetes. Identification of these novel genes and pathways may ultimately point to novel strategies for the diagnosis, treatment, and prevention of T2DM.